The Pima Indians of Arizona have the highest prevalence and incidence rate of noninsulin dependent diabetes mellitus (NIDDM) of any population in the world. We have been longitudinally studying a subset of this population that is at the highest risk of developing the disease. The purposes of the study are to 1) determine the metabolic characteristic which is most predictive of the subsequent development of NIDDM among non diabetics, and 2) to document the sequence of metabolic events that occur with the transition from normal to impaired glucose tolerance and subsequently to severe hyperglycemia and NIDDM. Subjects are admitted to the clinical research ward for approximately 7-10 days to undergo a variety of in vivo tests to assess insulin action and glucose metabolism. Subcutaneous adipocytes are obtained for in vitro studies of insulin and glucose metabolism as well. The results to date have shown that hyperinsulinemia and insulin resistance appear to be predictors of the development of NIDDM. The insulin resistance is not totally attributable to degree of obesity and may well have a genetic basis. The transition from normal to impaired glucose tolerance is associated with some worsening of in vivo insulin action as well as with weight gain. The insulin response to this development of insulin resistance appears to be appropriate for the degree of glycemia such that impaired glucose tolerance is not associated with any discernable abnormalities of insulin secretion.